Receptors for the Fc portions of immunoglobulins are important in triggering many of the protective functions of monocytes, macrophages and polymorphonuclear cells. Receptors for IgG (Fc.gamma. receptors or Fc.gamma.R) on these cells have been extensively investigated and bispecific molecules targeting these receptors have been constructed. (See e.g. European Patent No. 0 255 249 entitled "Monoclonal Antibodies to Fc Receptor for Immunoglobulin G on Human Mononuclear Phagocytes", which is co-owned by Applicants.) In addition, clinical trials of bispecific molecules (BsAb) which have specificity for the Fc.gamma.R and the HER-2/neu antigen, which is found on breast or ovarian cancers, indicate that these molecules are both safe and efficacious (Valone, Frank H. et al. 1995, J. of Clin. Oncol. 13(9): 2281-2292).
IgA receptors Fc.alpha. receptors (Fc.alpha.R or CD89) are also capable of promoting effector cell function. Binding of ligand to Fc.alpha.R triggers phagocytosis and antibody mediated cell cytotoxicity in leukocytes and Fc.alpha.R-bearing cell lines. Fc.alpha. receptors can also cooperate with receptors for IgG on effector cells in enhancing the phagocytosis of target cells. Monoclonal antibodies of the IgM (Shen, L. et al., 1989 J. Immunol. 143: 4117) and IgG (Monteiro, R. C. et al., 1992 J. Immunol, 148: 1764) classes have been developed against Fc.alpha.R.
IgA is abundant in the human body (Kerr, M. A. 1990, Biochem. J. 271:285-296). A single class of IgA Fc receptor, Fc.alpha.RI or CD89, which binds to monomeric IgA has been identified and characterized (Albrechtsen, M. et al., 1988 Immunol. 64:201; Monteiro R., et al., 1990 J. Exp. Med., 171:597). Fc.alpha.RI is constitutively expressed primarily on cytotoxic immune effector cells including monocytes, macrophages, neutrophils, and eosinophils (Morton, H. C., et al., 1996 Critical Reviews in Immunology 16:423). Fc.alpha.RI expression on a sub-population of lymphocytes (Morton, H. C., et al., 1996 Critical Reviews in Immunology 16:423), and on glomerular mesangial cells has been reported (Gomez-Guerrero, C., et al., 1996 J. Immunol. 156:4369-4376). Its expression on monocytes and PMN can be enhanced by TNF-.alpha. (Gesl, A., et al., 1994 Scad. J. Immunol. 39:151-156; Hostoffer, R. W., et al., 1994, The J. Infectious Diseases 170:82-87), IL-1, GM-CSF, LPS or phorbol esters (Shen L., et al., J. Immunol. 152:4080-4086; Schiller, C. A. et al., 1994, Immunology, 81:598-604), whereas IFN-.gamma. and TGF.beta.1 decrease Fc.alpha.RI expression (Reterink, T. J. F., et al., 1996, Clin. Exp. Immunol. 103:161-166). The .alpha.-chain of human Fc.alpha.RI is a heavily glycosylated, type one transmembrane molecule belonging to the Ig super-gene family which also includes receptors for IgG and IgE. One gene located on chromosome 19 encodes several alternatively spliced isoforms of the Fc.alpha.RI alpha chain (55-110 kDa; Morton, H. C., et al., 1996 Critical Reviews in Immunology 16:423). Myelocytic Fc.alpha.RI has been shown to be associated with the FcR .gamma.-chain which is implicated as playing a role in Fc.alpha.RI signal transduction (Morton, H. C. et al. 1995, J. Biol. Chem. 270:29781; Pfefferkorn, L. C., et al. 1995, J. Immunol., 153:3228-3236, Saito, K. et al., 1995, J. Allergy Clin. Immunol. 96:1152).
Fc.alpha.RI binds both antigen-complexed and monomeric IgA1 and IgA2 (Mazangera, R. L. et al., 1990 Biochem. J. 272:159-165), consistent with the receptor being saturated in vivo with monomeric IgA in the same manner as Fc.gamma.R and Fc.epsilon.RI are saturated with IgG and IgE respectively. Cross-linking Fc.alpha.RI on myeloid effector cells, by polymeric IgA, IgA immune complexes, or mAb specific for epitopes within or outside the ligand binding domain, stimulates degranulation, superoxide release, secretion of inflammatory cytokines, endocytosis and phagocytosis (Patty, C., A. Herbelin, A. Lihuen, J. F. Bach, and R. C. Monteiro. 1995 Immunology. 86:1-5; Stewart, W. W., R. L. Maz Yegera, L. Shen, and M. A. Kerr. 1994 J. Leucocyte Biology. 56:481-487; Stewart, W. W., and M. A. Kerr. 1990. Immunology. 71:328-334; Shen, L. 1992. J. Leukocyte Biology. 51 :373-378.). These physiological responses triggered via Fc.alpha.RI can be important in the first line of humoral defense on mucosal surfaces (Morton, H. C., M. van Egmond, and J. G. J. van de Winkel. 1996 Critical Reviews in Immunology. 16:423).
Thus Fc.alpha.RI is a clinically relevant trigger receptor on cytotoxic immune effector cells and its activity can be exploited to develop novel immunotherapies. The cytotoxic potential of Fc.alpha.RI has not been carefully explored since almost all monoclonal antibody (mAb) based therapies are being developed with mAbs of IgG class which do not bind to Fc.alpha.RI.